Methods for treating neurodegenerative disorders

ABSTRACT

Methods of treating a disease characterized by amyloid aggregates are provided herein.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/463,421, filed Feb. 24, 2018, then entire contents of which areincorporated herein by reference.

BACKGROUND

Alzheimer's disease (AD) is a progressive degenerative disease of thebrain primarily associated with aging. Prevalence of AD in the UnitedStates today is close to 5.1 Million. It was estimated that about one inten individuals over 65 and nearly half of those over 85 are affected byAlzheimer's disease. Approximately 360,000 patients will be diagnosedwith AD each year in the United States alone. Clinical presentation ofAD is characterized by loss of memory, cognition, reasoning, judgment,and orientation. As the disease progresses, motor, sensory, andlinguistic abilities are also affected until there is global impairmentof multiple cognitive functions. These cognitive losses occur gradually,but typically lead to severe impairment and eventual death in the rangeof four to twelve years.

Alzheimer's disease is characterized by two major pathologicobservations in the brain: beta amyloid plaques (neuritic plaques) andneurofibrillary tangles. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy), and later also byabnormally phosphorylated tau protein (neurofibrillary tangles). RecentAD research suggests that soluble oligomeric AP constitute mainneurotoxic species.

Amyloid plaques and other amyloid and amyloid-type aggregates are alsocharacteristic of other diseases, such as Down's syndrome dementia,Parkinson's Disease, Acute macular degeneration (AMD), glaucoma,Inclusion Body Myositis (IBM), traumatic brain injury, Lewy Bodiesdementia, Huntington's disease, Nieman-Picks Type C, Cerebral AmyloidAngiopathy (CAA), Creutzfeldt-Jakob disease, AA Amyloidosis, ALAmyloidosis, ATTR amyloidosis, Familial amyloid polyneuropathy (FAP),Familial amyloid cardiomyopathy (FAC), Senile systemic amyloidosis, andprion disease. There is currently a lack of pharmaceutical agents thatdisaggregate and/or prevent formation of these unwanted aggregates.

Tramiprosate, 3-amino-1-propanesulfonic acid (3APS) is an oral amyloidanti-aggregation agent which reduces amyloid beta oligomerneurotoxicity. The tramiprosate Phase 3 trials in mild-to-moderate ADshowed an excellent drug profile, including the capability to slow thereduction of brain hippocampal volume, and to improve brain cognitionand function in subset analyses. See e.g., Gauthier, S. et al. Effect oftramiprosate in patients with mild-to-moderate Alzheimer's disease:exploratory analyses of the MRI sub-group of the Alphase study. J NutrHealth Aging 13, 550-557 (2009); Saumier, D., Duong, A., Haine, D.,Garceau, D. & Sampalis, J. Domain-specific cognitive effects oftramiprosate in patients with mild to moderate Alzheimer's disease:ADAS-cog subscale results from the Alphase Study. J Nutr Health Aging13, 808-812 (2009); and Aisen, P. S. et al. Tramiprosate inmild-to-moderate Alzheimer's disease—a randomized, double-blind,placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci7, 102-111 (2011). More recently, it has been shown that tramiprosateprevents the formation of Aß42 oligomers, and thus reduces amyloidtoxicity, through a novel enveloping mechanism of action.

ALZ-801 (3-(2-amino-3-methylbutanamido)propane-1-sulfonic acid), a newprodrug of 3-amino-1-propanesulfonic acid (3APS, Tramiprosate) is apromising product which provides more consistent plasma exposures andimproved GI tolerability then tramiprosate. ALZ-801 is currently inclinical development for treatment of AD.

Despite the great potential of ALZ-801, the need remains for the use ofadditional agents for preventing and treating amyloid-related diseasessuch as Alzheimer's disease.

SUMMARY

Provided herein is the use of a compound of structural formula I:

or a pharmaceutically acceptable salt thereof, for treating a diseasecharacterized by amyloid aggregates, wherein the variables A, R¹, R²,R³, and R⁴ are as described herein.

Also provided is the use of a compound of structural formula II:

or a pharmaceutically acceptable salt thereof, for treating a diseasecharacterized by amyloid aggregates, wherein the variables B, R⁷, R⁸ R⁹,and R¹⁰ are as described herein.

Also provided is the use of a compound of structural formula III:

or a pharaceutically acceptable salt thereof, for treating a diseasecharacterized by amyloid aggregates, wherein the variables D, q, and R¹⁶are as described herein.

Also provided is the use of a compound of structural formula IV:

or a pharmaceutically acceptable salt thereof, for treating a diseasecharacterized by amyloid aggregates, wherein the variables E, t, and R¹⁷are as described herein.

Further provided is the use of a pharmaceutical composition comprising acompound of structural formula I, II, III, or IV or a pharmaceuticallyacceptable salt thereof, for treating a disease characterized by amyloidand amyloid-like aggregates (e.g., Alzheimer's disease).

Diseases characterized by amyloid and amyloid-like aggregates includethose described herein.

DETAILED DESCRIPTION 1. Definitions

As used herein, a hyphen (“-”) at the beginning or end of a recitedgroup designates the point at which a recited group is attached to adefined group. For example, —SO₂—(C₁-C₃)alkyl-(C₂-C₆)cycloalkyl meansthat the group is attached via the sulfonyl.

The term “alkylene” refers to a straight or branched bivalent alkylgroup.

The term “C₀ alkylene” as used herein means a bond. Thus, a moietydefined herein as “—(C₀-C₆ alkylene)-aryl” includes both -aryl (i.e., C₀alkylene-aryl) and —(C₁-C₆ alkylene)-aryl.

The term “alkenylene” refers to a straight or branched bivalent alkenylgroup.

The term “alkynylene” refers to a straight or branched bivalent alkynylgroup.

The term “alkyl”, used alone or as a part of a larger moiety such ase.g., “haloalkyl”, means a saturated monovalent straight or branchedhydrocarbon radical having, unless otherwise specified, 1-10 carbonatoms and includes, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl and the like.

The term “alkenyl”, used alone or as a part of a larger moiety such ase.g., “haloalkenyl”, means a monovalent group derived from a straight-or branched-chain aliphatic moiety having at least one carbon-carbondouble bond having, unless otherwise specified 1-10 carbon atoms.Representative alkenyl groups include, but are not limited to, ethenyl(“vinyl”), propenyl (“allyl”), butenyl, 1-methyl-2-buten-1-yl, and thelike.

The term “alkynyl”, used alone or as a part of a larger moiety such ase.g., “haloalkynyl”, means a monovalent group derived from a straight-or branched-chain aliphatic moiety having at least one carbon-carbontriple bond having, unless otherwise specified 1-10 carbon atoms.Representative alkynyl groups include, but are not limited to, ethynyl,2-propynyl (“propargyl”), 1-propynyl, and the like.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), and iodine (iodo, —I).

The term “carbocyclyl” (also referred to herein as “carbocycle”“cycloaliphatic” or “cycloalkyl”), as used herein, means a monocyclichydrocarbon or bicyclic hydrocarbon that is completely saturated.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic carbon ring systems having a total of five to 10 ring members,wherein at least one ring in the system is aromatic. The term “aryl” maybe used interchangeably with the term “aryl ring”. In certainembodiments, “aryl” refers to an aromatic ring system which includes,but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like.It will be understood that when specified, optional substituents on anaryl group may be present on any substitutable position.

The term “heteroaryl” used alone or as part of a larger moiety as in“heteroarylalkyl”, “heteroarylalkoxy”, or “heteroarylaminoalkyl”, refersto a 5- to 12-membered aromatic radical containing 1-4 heteroatomsselected from N, O, and S. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or“heteroaromatic”. A heteroaryl group may be mono- or bi-cyclic.Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, and pyrazinyl. Bi-cyclic heteroaryls includegroups in which a monocyclic heteroaryl ring is fused to one or morearyl or heteroaryl rings. Nonlimiting examples include indolyl,benzoxazolyl, benzoxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl,thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.It will be understood that when specified, optional substituents on aheteroaryl group may be present on any substitutable position and,include, e.g., the position at which the heteroaryl is attached. In oneaspect, the term “heteroaryl” also includes ring systems containing aquarternary nitrogen. One example of such a compound is Compound 165,herein:

The term “heterocyclyl” means a 4- to 12-membered saturated or partiallyunsaturated heterocyclic ring containing 1 to 4 heteroatomsindependently selected from N, O, and S. The terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein. Aheterocyclyl ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. A heterocyclyl groupmay be mono- or bicyclic. Examples of monocyclic saturated or partiallyunsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl,pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl,dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl,dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, andtetrahydropyrimidinyl. Bi-cyclic heterocyclyl groups include, e.g.,unsaturated heterocyclic radicals fused to another unsaturatedheterocyclic radical, cycloalkyl, or aromatic or heteroaryl ring, suchas for example, benzodioxolyl, dihydrobenzodioxinyl,6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 1,2-dihydroquinolinyl,dihydrobenzofuranyl, tetrahydronaphthyridine, indolinone,dihydropyrrolotriazole, quinolinone, dioxaspirodecane. It will beunderstood that when specified, optional substituents on a heterocyclylgroup may be present on any substitutable position and, include, e.g.,the position at which the heterocyclyl is attached.

The compounds described herein may have chiral centers and/or geometriccenters (E- and Z-isomers). It will be understood that the presentdisclosure encompasses all stereoisomers and geometric isomers.Tautomeric forms of the compounds described herein are also part of thepresent disclosure.

The compounds described herein may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds described herein refer to non-toxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.Example of pharmaceutically acceptable salts are also described, forexample, in Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 66, 119 (1977). Such salts include e.g., (1) acid addition salts, formed on abasic or positively charged functionality, by the addition of inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonateforming agents, and the like; or formed with organic acids such asacetic acid, propionic acid, lactic acid, oxalic, glycolic acid, pivalicacid, t-butylacetic acid, p-hydroxybutyric acid, valeric acid, hexanoicacid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinicacid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2 hydroxyethanesulfonic acid, cyclohexylaminosulfonic acid,benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2naphthalenesulfonic acid, 4 toluenesulfonic acid, camphorsulfonic acid,3-phenyl propionic acid, lauryl sulphonic acid, lauryl sulfuric acid,oleic acid, palmitic acid, stearic acid, lauric acid, embonic (pamoic)acid, palmitiic acid, pantothenic acid, lactobionic acid, alginic acid,galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid,glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid,ascorbic acid, stearic acid, muconic acid, and the like; and (2) baseaddition salts, formed when an acidic proton present in the parentcompound either is replaced by a metal ion, including, an alkali metalion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g.magnesium, calcium, barium), or other metal ions such as aluminum, zinc,iron and the like; or coordinates with an organic base such as ammonia,ethylamine, diethylamine, ethylenediamine, N,N′-dibenzylethylenediamine,ethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysineand the like. In one aspect, pharmaceutically acceptable salts include,when appropriate, nontoxic ammonium, quaternary ammonium, and aminecations formed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

“Pharmaceutically acceptable” refers to drugs, medicaments, inertingredients etc., which the term describes, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,incompatibility, instability, irritation, allergic response, and thelike, commensurate with a reasonable benefit/risk ratio. In one aspect,pharmaceutically acceptable refers to a compound or composition that isapproved or approvable by a regulatory agency of the Federal or stategovernment or listed in the U.S. Pharmacopoeia or other generallyrecognized pharmacopoeia for use in animals and more particularly inhumans.

The term “pharmaceutically acceptable carrier” refers to a non-toxiccarrier, adjuvant, or vehicle that does not destroy the pharmacologicalactivity of the compound with which it is formulated. Pharmaceuticallyacceptable carriers, adjuvants or vehicles that may be used in thecompositions of this disclosure include, but are not limited to, organicor inorganic carriers, excipients or diluents suitable forpharmaceutical applications.

As used herein the terms “subject” and “patient” may be usedinterchangeably, and means a mammal in need of treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals (e.g.,cows, pigs, horses, sheep, goats and the like) and laboratory animals(e.g., rats, mice, guinea pigs and the like). Typically, the subject isa human in need of treatment.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease, or one or more symptoms thereof, as describedherein. In some embodiments, treatment may be administered after one ormore symptoms have developed, i.e., therapeutic treatment. In otherembodiments, treatment may be administered in the absence of symptoms.For example, treatment may be administered to a susceptible individualprior to the onset of symptoms (e.g., in light of a history of symptomsand/or in light of genetic or other susceptibility factors), i.e.,prophylactic treatment. Treatment may also be continued after symptomshave resolved, for example to prevent or delay their recurrence.

2. Compounds of the Present Methods

In a first embodiment, provided herein is a method of treating a diseasecharacterized by amyloid aggregates comprising the step of administeringto a subject in need thereof a compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a 6-membered aryl or a 6-membered heteroaryl comprising 1-3nitrogen heteroatoms;

R¹ is selected from —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, and —(C₂-C₆ alkynylene)-S(O)₂—OH;

R² is selected from hydrogen, —C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —(C₀-C₆alkylene)-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-C(O)—N(R⁵)(R⁶), —(C₀-C₆alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl)-, —(C₂-C₆alkenylene)-N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkynylene)-N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkenylene)-aryl-N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-aryl-C(O)—N(R⁵)(R⁶),—(C₂-C₆ alkenylene)-aryl-C(O)—OH, —(C₂-C₆ alkynylene)-aryl-N(R⁵)(R⁶),—(C₂-C₆ alkynylene)-aryl-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkynylene)-aryl-C(O)—OH, —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, —(C₂-C₆ alkynylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-aryl-S(O)₂—OH, —(C₂-C₆ alkynylene)-aryl-S(O)₂—OH, —(C₀-C₆alkylene)-aryl, —(C₀-C₆ alkylene)-heteroaryl, —(C₀-C₆alkylene)-heterocyclyl, and —(C₀-C₆ alkylene)-carbocyclyl, wherein up tothree methylene units in the C₀-C₆ alkylene portion of any —(C₀-C₆alkylene)-aryl, —(C₀-C₆ alkylene)-heteroaryl, —(C₀-C₆alkylene)-heterocyclyl, or —(C₀-C₆ alkylene)-carbocyclyl are optionallyand independently replaced with —S—, —O—, —NH—, or —N(C₁-C₄ alkyl)-; andany aryl, heteroaryl, heterocyclyl, or carbocyclyl portion of R² isoptionally substituted with up to 4 substituents independently selectedfrom halo, oxo, —CN, —OH, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —(C₀-C₆alkylene)-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-C(O)—N(R⁵)(R⁶), —(C₀-C₆alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkenylene)-N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkynylene)-N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₆alkylene)-S(O)₂—OH, —(C₂-C₆ alkenylene)-S(O)₂—OH, —(C₂-C₆alkynylene)-S(O)₂—OH, and —(C₀-C₆ alkylene)-aryl-S(O)₂—OH;

R³ is a substituent bound to a carbon ring atom in ring A and isselected from hydrogen, halogen, —CN, —OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl,—(C₀-C₆ alkylene)-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-C(O)—N(R⁵)(R⁶), —(C₀-C₆alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkenylene)-N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkynylene)-N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₆alkylene)-aryl-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-aryl-C(O)-aryl-N(R⁵)(R⁶),—(C₀-C₆ alkylene)-aryl-C(O)—OH, —(C₂-C₆ alkenylene)-aryl-N(R⁵)(R⁶),—(C₂-C₆ alkenylene)-aryl-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkenylene)-aryl-C(O)—OH, —(C₂-C₆ alkynylene)-aryl-N(R⁵)(R⁶), —(C₂-C₆alkynylene)-aryl-C(O)—N(R⁵)(R⁶), and —(C₂-C₆ alkynylene)-aryl-C(O)—OH;

R⁴ is selected from hydrogen, —OH, C₁-C₄ alkyl, N(R⁵)(R⁶), and phenyloptionally substituted with halogen or hydroxy; and when R³ and R⁴ areattached to adjacent ring atoms, R³ and R⁴ are optionally taken togetherto form a carbocycle, aryl, heterocycle or heteroaryl fused to ring A,wherein the carbocycle, aryl, heterocycle or heteroaryl is optionallysubstituted with one or more substituents independently selected fromhalo, oxo, —CN, —OH, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —(C₀-C₆alkylene)-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-C(O)—N(R⁵)(R⁶), —(C₀-C₆alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkenylene)-N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkynylene)-N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₆alkylene)-S(O)₂—OH, —(C₂-C₆ alkenylene)-S(O)₂—OH, —(C₂-C₆alkynylene)-S(O)₂—OH, and —(C₀-C₆ alkylene)-aryl, wherein the arylportion of the substituent is optionally substituted one or twosubstituents independently selected from —S(O)₂—OH and —N(R⁵)(R⁶);

each R⁵ is independently selected from hydrogen, —C(O)—(C₁-C₄ alkyl),and —C₁-C₄ alkyl; and

each R⁶ is independently selected from hydrogen, —C₁-C₄ alkyl, —(C₀-C₄alkylene)-carbocycle, —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-heterocycle, and —(C₀-C₄ alkylene)-heteroaryl, and wherein thecarbocyclyl, aryl, heteroaryl, or heterocyclyl portion of R⁶ may befurther substituted with up to 4 substituents independently selectedfrom halogen, —CN, —OH, —COOH, —CONH₂, and C₁-C₃ alkyl; or R⁵ and R⁶together form a heterocyclic or heteroaromatic ring optionallysubstituted with one or more groups selected from halogen, oxo, —NH₂,—NH(C₁—C₄ alkyl), —N(C₁-C₄ alkyl)₂, —CN, —OH, —COOH, —CONH₂, and C₁-C₃alkyl;

provided the compound comprises no more than two —S(O)₂—OH moieties.

In a second embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a 6-membered aryl or heteroaryl comprising 1-3 nitrogenheteroatoms;

R¹ is selected from —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, and —(C₂-C₆ alkynylene)-S(O)₂—OH;

R² is selected from hydrogen, —(C₀-C₆ alkylene)-N(R⁵)(R⁶), —(C₀-C₆alkylene)-C(O)—N(R⁵)(R⁶), —(C₀-C₆ alkylene)-C(O)—OH, —(C₂-C₆alkenylene)-N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkynylene)-N(R⁵)(R⁶), —(C₂-C₆alkynylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-C(O)—OH, —(C₀-C₆alkylene)-aryl-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-aryl-C(O)-aryl-N(R⁵)(R⁶),—(C₀-C₆ alkylene)-aryl-C(O)—OH, —(C₂-C₆ alkenylene)-aryl-N(R⁵)(R⁶),—(C₂-C₆ alkenylene)-aryl-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkenylene)-aryl-C(O)—OH, —(C₂-C₆ alkynylene)-aryl-N(R⁵)(R⁶), —(C₂-C₆alkynylene)-aryl-C(O)—N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-aryl-C(O)—OH,—(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆ alkenylene)-S(O)₂—OH, —(C₂-C₆alkynylene)-S(O)₂—OH, —(C₀-C₆ alkylene)-aryl-S(O)₂—OH, —(C₂-C₆alkenylene)-aryl-S(O)₂—OH, and —(C₂-C₆ alkynylene)-aryl-S(O)₂—OH;

R³ is a substituent bound to a carbon ring atom in ring A and isselected from hydrogen, halogen, —CN, —OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl,—(C₀-C₆ alkylene)-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-C(O)—N(R⁵)(R⁶), —(C₀-C₆alkylene)-C(O)—OH, —(C₂-C₆ alkenylene)-N(R⁵)(R⁶), —(C₂-C₆alkenylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-C(O)—OH, —(C₂-C₆alkynylene)-N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkynylene)-C(O)—OH, —(C₀-C₆ alkylene)-aryl-N(R⁵)(R⁶), —(C₀-C₆alkylene)-aryl-C(O)-aryl-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-aryl-C(O)—OH,—(C₂-C₆ alkenylene)-aryl-N(R⁵)(R⁶), —(C₂-C₆alkenylene)-aryl-C(O)—N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-aryl-C(O)—OH,—(C₂-C₆ alkynylene)-aryl-N(R⁵)(R⁶), —(C₂-C₆alkynylene)-aryl-C(O)—N(R⁵)(R⁶), and —(C₂-C₆ alkynylene)-aryl-C(O)—OH;

R⁴ is hydrogen and when R³ is hydrogen or C₁-C₃ alkyl, R⁴ isadditionally selected from C₁-C₃ alkyl and phenyl optionally substitutedwith halogen or hydroxy; and when R³ and R⁴ are attached to adjacentring atoms, R³ and R⁴ are optionally taken together to form acarbocycle, aryl, heterocycle or heteroaryl fused to ring A, wherein thecarbocycle, aryl, heterocycle or heteroaryl is optionally substitutedwith one or more substituent selected from halo, —CN, —OH, —(C₀-C₆alkylene)-N(R⁵)(R⁶), —(C₀-C₆ alkylene)-C(O)—N(R⁵)(R⁶), —(C₀-C₆alkylene)-C(O)—OH, —(C₂-C₆ alkenylene)-N(R⁵)(R⁶), —(C₂-C₆alkenylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆ alkenylene)-C(O)—OH, —(C₂-C₆alkynylene)-N(R⁵)(R⁶), —(C₂-C₆ alkynylene)-C(O)—N(R⁵)(R⁶), —(C₂-C₆alkynylene)-C(O)—OH, —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, —(C₂-C₆ alkynylene)-S(O)₂—OH, and —(C₀-C₆alkylene)-aryl-S(O)₂—OH;

each R⁵ is independently selected from hydrogen, —C(O)—(C₁-C₄ alkyl),and —C₁-C₄ alkyl; and

each R⁶ is independently selected from hydrogen, —C₁-C₄ alkyl, —(C₀-C₄alkylene)-carbocycle, —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-heterocycle, —(C₀-C₄ alkylene)-heteroaryl, and wherein thecarbocyclyl, aryl, heteroaryl, or heterocyclyl portion of R⁶ may befurther substituted with up to 4 substituents independently selectedfrom halogen, —CN, —OH, —COOH, —CONH₂, and C₁-C₃ alkyl; or R⁵ and R⁶together form a heterocyclic or heteroaromatic ring optionallysubstituted with one or more groups selected from halogen, —CN, —OH,—COOH, —CONH₂, and C₁-C₃ alkyl;

provided the compound comprises no more than two —S(O)₂—OH moieties.

In a third embodiment of the methods described herein, R¹ in structuralformula I or Ia is selected from —S(O)₂—OH and —CH₂—S(O)₂—OH, whereinthe remaining variables are as described above for structural formula Ior Ia. Alternatively, R¹ in structural formula I or Ia is bound to aring carbon and selected from —S(O)₂—OH and —CH₂—S(O)₂—OH, wherein theremaining variables are as described above for structural formula I orIa. In another alternative, R¹ in structural formula I or Ia is bound toa ring carbon and is —S(O)₂—OH, wherein the remaining variables are asdescribed above for structural formula I or Ia.

In a fourth embodiment of the methods described herein, R² in structuralformula I or Ia is selected from —NH₂, —CH₂NH₂, —C(O)NH₂, and —COOH,wherein the remaining variables are as described above for structuralformula I or Ia, or the third embodiment thereof. Alternatively, R² instructural formula I or Ia is bound to a ring carbon and selected from—CH₂NH₂, —CH₂COOH, and —CH₂C(O)NH₂, wherein the remaining variables areas described above for structural formula I or Ia, or third embodimentthereof. In another alternative, R² in structural formula I or Ia isbound to a ring carbon and is —NH₂, wherein the remaining variables areas described above for structural formula I or Ia, or third embodimentthereof.

In a fifth embodiment of the methods described herein, ring A instructural formula I or Ia is phenyl, wherein the remaining variablesare as described above for structural formula I or Ia, or the third orfourth embodiment thereof described above. In other aspects of the firstembodiment of the methods described herein, ring A in structural formulaI or Ia is selected from pyridine, pyrimidine, pyrazine, pyridazine, andtriazine, wherein the remaining variables are as described above forstructural formula I or Ia, or the third or fourth embodiment thereof

In a sixth embodiment, provided herein is a method of treating a diseasecharacterized by amyloid aggregates comprising the step of administeringto a subject in need thereof a compound of structural formula I-1

or a pharmaceutically acceptable salt thereof, wherein:

R¹¹ is —(C₀-C₄ alkylene)-SO₃ ⁻;

R¹² is selected from hydrogen, —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-heteroaryl, —(C₀-C₄ alkylene)-carbocyclyl, and —(C₀-C₄alkylene)-heterocyclyl

R¹³ is selected from hydrogen, C₁-C₆ alkyl, (C₀-C₆ alkylene)-NH₂, and(C₀-C₆ alkylene)-C(O)—NH₂; and

R¹⁴ is C₁-C₄ alkyl.

In a seventh embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula I, wherein R³ and R⁴ are taken together with ring A to form abicyclic ring quaternary nitrogen-containing ring system, wherein theremaining variables are as described above for structural formula I orIa or the third, fourth, or fifth embodiment thereof described above. Inone aspect of the seventh embodiment, R³ and R⁴ are taken together withring A to form a bicyclic ring system comprising one quaternarynitrogen, wherein the remaining variables are as described above forstructural formula I or Ia or the third, fourth, or fifth embodimentthereof described above. In some aspects of the seventh embodiment, thequaternary nitrogen is a ring atom in the ring A portion of the bicyclicring system, wherein the remaining variables are as described above forstructural formula I or Ia. In some aspects of the seventh embodiment,the quaternary nitrogen is a bridgehead atom in the bicyclic ringsystem, wherein the remaining variables are as described above forstructural formula I or Ia or the third, fourth, or fifth embodimentthereof described above. In some aspects of the seventh embodiment, thequaternary nitrogen is a ring atom in the portion of the bicyclic ringsystem formed by taking R³ and R⁴ together, wherein the remainingvariables are as described above for structural formula I or Ia or thethird, fourth, or fifth embodiment thereof described above. In someaspects of the seventh embodiment, the quaternary nitrogen, whensubstitutable, is substituted with R⁴, wherein the remaining variablesare as described above for structural formula I or Ia or the third,fourth, or fifth embodiment thereof described above. In some aspects ofthe seventh embodiment, the quaternary nitrogen, when substitutable, issubstituted with a C₁-C₄ alkyl, wherein the remaining variables are asdescribed above for structural formula I or Ia or the third, fourth, orfifth embodiment thereof described above. In some aspects of the seventhembodiment, the compound of structural formula I has the formula:

or a pharmaceutically acceptable salt thereof, wherein:

ring C is a ring formed by taking together R³ and R⁴, wherein ring Coptionally comprises 1 to 2 ring nitrogen atoms in addition to thequaternary nitrogen;

ring D is a ring formed by taking together R³ and R⁴, wherein ring Doptionally comprises 1 to 2 ring heteroatoms selected from S, O and N inaddition to the quaternary nitrogen;

R¹¹ is —(C₀-C₄ alkylene)-SO₃ ⁻;

R¹² is selected from hydrogen, —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-heteroaryl, —(C₀-C₄ alkylene)-carbocyclyl, and —(C₀-C₄alkylene)-heterocyclyl; and

R¹⁵ is C₁-C₄ alkyl.

In an eighth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula I or Ia, or a pharmaceutical salt thereof, wherein:

ring A is selected from pyridine and pyrimidine;

R¹ is selected from —(C₀-C₄ alkylene)-S(O)₂—OH, —(C₂-C₄alkenylene)-S(O)₂—OH, and —(C₂-C₄ alkynylene)-S(O)₂—OH;

R² is selected from —(C₀-C₆ alkylene)-NH₂, —(C₂-C₄ alkenylene)-NH₂, and—(C₂-C₄ alkynylene)-NH₂;

R³ is selected from hydrogen and C₁-C₆ alkyl; and

R⁴ is hydrogen.

In a ninth embodiment, provided herein is a method of treating a diseasecharacterized by amyloid aggregates comprising the step of administeringto a subject in need thereof a compound of structural formula I or Ia,wherein R¹ is —S(O)₂—OH; and R² is —NH₂; and wherein the remainingvariables are as described above for structural formula I or Ia or thethird, fourth, fifth, or eighth embodiment thereof described above.

In a tenth embodiment, provided herein is a method of treating a diseasecharacterized by amyloid aggregates comprising the step of administeringto a subject in need thereof a compound of structural formula I or Ia,wherein ring A comprises a quaternary nitrogen ring atom substitutedwith C₁-C₄ alkyl; and R¹ is —SO₃ ⁻; and wherein the remaining variablesare as described above for structural formula I or Ia or the third,fourth, fifth, eighth, or ninth embodiment thereof described above.

In an eleventh embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula I or Ia, wherein R¹ is —SO₃ ⁻; and R² is selected fromheteroaryl and heterocyclyl; and R² comprises a quaternary nitrogen ringatom; and wherein the remaining variables are as described above forstructural formula I or Ia or the third, fourth, fifth, eighth, ninth,or tenth embodiment thereof described above.

In a twelfth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula II:

or pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-membered heteroaromatic ring comprising 1-3 heteroatoms,wherein:

-   -   the first heteroatom is N, or S or S(O)₂;    -   the second heteroatom, if present, is N or O, wherein when the        first heteroatom is S or S(O)₂, the second heteroatom is N; and    -   the third heteroatom, if present, is N;

R⁷ is selected from —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, and —(C₂-C₆ alkynylene)-S(O)₂—OH;

R⁸ is selected from hydrogen, —C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —(C₀-C₆alkylene)-N(R¹⁰)(R¹¹), —(C₀-C₆ alkylene)-C(O)—N(R¹⁰)(R¹¹), —(C₀-C₆alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl)-, —(C₂-C₆alkenylene)-N(R¹⁰)(R¹¹), —(C₂-C₆ alkenylene)-C(O)—N(R¹⁰)(R¹¹), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkynylene)-N(R¹⁰)(R¹¹), —(C₂-C₆ alkynylene)-C(O)—N(R¹⁰)(R¹¹), —(C₂-C₆alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkenylene)-aryl-N(R¹⁰)(R¹¹), —(C₂-C₆ alkenylene)-aryl-C(O)—N(R¹⁰)(R¹¹),—(C₂-C₆ alkenylene)-aryl-C(O)—OH, —(C₂-C₆ alkynylene)-aryl-N(R¹⁰)(R¹¹),—(C₂-C₆ alkynylene)-aryl-C(O)—N(R¹⁰)(R¹¹), —(C₂-C₆alkynylene)-aryl-C(O)—OH, —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, —(C₂-C₆ alkynylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-aryl-S(O)₂—OH, —(C₂-C₆ alkynylene)-aryl-S(O)₂—OH, —(C₀-C₆alkylene)-aryl, —(C₀-C₆ alkylene)-heteroaryl, —(C₀-C₆alkylene)-heterocyclyl, and —(C₀-C₆ alkylene)-carbocyclyl, wherein up tothree methylene units in the C₀-C₆ alkylene portion of any —(C₀-C₆alkylene)-aryl, —(C₀-C₆ alkylene)-heteroaryl, —(C₀-C₆alkylene)-heterocyclyl, or —(C₀-C₆ alkylene)-carbocyclyl are optionallyand independently replaced with —S—, —O—, —NH—, or —N(C₁-C₄ alkyl)-; andany aryl, heteroaryl, heterocyclyl, or carbocyclyl portion of R² isoptionally substituted with up to 4 substituents independently selectedfrom halo, oxo, —CN, —OH, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), —(C₀-C₆alkylene)-N(R¹⁰)(R¹¹), —(C₀-C₆ alkylene)-C(O)—N(R¹⁰)(R¹¹), —(C₀-C₆alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkenylene)-N(R¹⁰)(R¹¹), —(C₂-C₆ alkenylene)-C(O)—N(R¹⁰)(R¹¹), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)—O—(C₁-C₄ alkyl), —(C₂-C₆alkynylene)-N(R¹⁰)(R¹¹), —(C₂-C₆ alkynylene)-C(O)—N(R¹⁰)(R¹¹), —(C₂-C₆alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl), —(C₀-C₆alkylene)-S(O)₂—OH, —(C₂-C₆ alkenylene)-S(O)₂—OH, —(C₂-C₆alkynylene)-S(O)₂—OH, and —(C₀-C₆ alkylene)-aryl-S(O)₂—OH;

R⁹ is a substituent bound to a carbon ring atom in ring B and isselected from hydrogen, halogen, —CN, —OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl,—(C₀-C₆ alkylene)-N(R¹⁰)(R¹¹), —(C₀-C₆ alkylene)-C(O)—N(R¹⁰)(R¹¹),—(C₀-C₆ alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl),—(C₂-C₆ alkenylene)-N(R¹⁰)(R¹¹), —(C₂-C₆ alkenylene)-C(O)—N(R¹⁰)(R¹¹),—(C₂-C₆ alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)—O—(C₁-C₄ alkyl),—(C₂-C₆ alkynylene)-N(R¹⁰)(R¹¹), —(C₂-C₆ alkynylene)-C(O)—N(R¹⁰)(R¹¹),—(C₂-C₆ alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl),—(C₀-C₆ alkylene)-aryl-N(R¹⁰)(R¹¹), —(C₀-C₆alkylene)-aryl-C(O)-aryl-N(R¹⁰)(R¹¹), —(C₀-C₆ alkylene)-aryl-C(O)—OH,—(C₂-C₆ alkenylene)-aryl-N(R¹⁰)(R¹¹), —(C₂-C₆alkenylene)-aryl-C(O)—N(R¹⁰)(R¹¹), —(C₂-C₆ alkenylene)-aryl-C(O)—OH,—(C₂-C₆ alkynylene)-aryl-N(R¹⁰)(R¹¹), —(C₂-C₆alkynylene)-aryl-C(O)—N(R¹⁰)(R¹¹), and —(C₂-C₆ alkynylene)-aryl-C(O)—OH;

R¹⁰ is selected from hydrogen, —OH, C₁-C₄ alkyl, N(R¹⁰)(R¹¹), and phenyloptionally substituted with halogen or hydroxy; and when R⁹ and R¹⁰ areattached to adjacent ring atoms, R⁹ and R¹⁰ are optionally takentogether to form a carbocycle, aryl, heterocycle or heteroaryl fused toring A, wherein the carbocycle, aryl, heterocycle or heteroaryl isoptionally substituted with one or more substituents independentlyselected from halo, oxo, —CN, —OH, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl),—(C₀-C₆ alkylene)-N(R¹¹)(R¹²), —(C₀-C₆ alkylene)-C(O)—N(R¹¹)(R¹²),—(C₀-C₆ alkylene)-C(O)—OH, —(C₀-C₆ alkylene)-C(O)—O—(C₁-C₄ alkyl),—(C₂-C₆ alkenylene)-N(R¹¹)(R¹²), —(C₂-C₆ alkenylene)-C(O)—N(R¹⁰)(R¹¹),—(C₂-C₆ alkenylene)-C(O)—OH, —(C₂-C₆ alkenylene)-C(O)-0-(C₁-C₄ alkyl),—(C₂-C₆ alkynylene)-N(R¹⁰)(R¹¹), —(C₂-C₆ alkynylene)-C(O)—N(R¹⁰)(R¹¹),—(C₂-C₆ alkynylene)-C(O)—OH, —(C₂-C₆ alkynylene)-C(O)—O—(C₁-C₄ alkyl),—(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆ alkenylene)-S(O)₂—OH, —(C₂-C₆alkynylene)-S(O)₂—OH, and —(C₀-C₆ alkylene)-aryl, wherein the arylportion of the substituent is optionally substituted one or twosubstituents independently selected from —S(O)₂—OH and —N(R¹⁰)(R¹¹);

each R¹¹ is independently selected from hydrogen, —C(O)—(C₁-C₄ alkyl),and —C₁-C₄ alkyl;

each R¹² is independently selected from hydrogen, —C₁-C₄ alkyl, —(C₀-C₄alkylene)-carbocycle, —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-heterocycle, and —(C₀-C₄ alkylene)-heteroaryl, and wherein thecarbocyclyl, aryl, heteroaryl, or heterocyclyl portion of R² may befurther substituted with up to 4 substituents independently selectedfrom halogen, —CN, —OH, —COOH, —CONH₂, and C₁-C₃ alkyl; or R¹¹ and R¹²together form a heterocyclic or heteroaromatic ring optionallysubstituted with one or more groups selected from halogen, oxo, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —CN, —OH, —COOH, —CONH₂, and C₁-C₃alkyl;

provided the compound comprises no more than two —S(O)₂—OH moieties.

In a thirteenth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-membered heteroaromatic ring comprising 1-3 heteroatoms,wherein:

-   -   the first heteroatom is N, or S or S(O)₂;    -   the second heteroatom, if present, is N or O, wherein when the        first heteroatom is S or S(O)₂, the second heteroatom is N; and    -   the third heteroatom, if present, is N;

R⁷ is selected from —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, and —(C₂-C₆ alkynylene)-S(O)₂—OH;

R⁸ is selected from —(C₀-C₆ alkylene)-N(R¹¹)(R¹²), —(C₀-C₆alkylene)-C(O)—N(R¹¹)(R²), —(C₀-C₆ alkylene)-C(O)—OH, —(C₂-C₆alkenylene)-N(R¹¹)(R¹²), —(C₂-C₆ alkenylene)-C(O)—N(R¹¹)(R¹²), —(C₂-C₆alkenylene)-C(O)—OH, —(C₂-C₆ alkynylene)-N(R¹¹)(R¹²), —(C₂-C₆alkynylene)-C(O)—N(R¹¹)(R¹²), —(C₂-C₆ alkynylene)-C(O)—OH, —(C₀-C₆alkylene)-aryl-N(R¹¹)(R¹²), —(C₀-C₆alkylene)-aryl-C(O)-aryl-N(R¹¹)(R¹²), —(C₀-C₆ alkylene)-aryl-C(O)—OH,—(C₂-C₆ alkenylene)-aryl-N(R¹¹)(R¹²), —(C₂-C₆alkenylene)-aryl-C(O)—N(R¹¹)(R¹²), —(C₂-C₆ alkenylene)-aryl-C(O)—OH,—(C₂-C₆ alkynylene)-aryl-N(R¹¹)(R¹²), —(C₂-C₆alkynylene)-aryl-C(O)—N(R¹¹)(R¹²), —(C₂-C₆ alkynylene)-aryl-C(O)—OH,—(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆ alkenylene)-S(O)₂—OH, —(C₂-C₆alkynylene)-S(O)₂—OH, —(C₀-C₆ alkylene)-aryl-S(O)₂—OH, —(C₂—C₆alkenylene)-aryl-S(O)₂—OH, and —(C₂-C₆ alkynylene)-aryl-S(O)₂—OH;

R⁹ is a substituent bound to a carbon ring atom in ring B and isselected from hydrogen, halogen, —CN, —OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl,—(C₀-C₆ alkylene)-N(R¹¹)(R¹²), —(C₀-C₆ alkylene)-C(O)—N(R¹¹)(R¹²),—(C₀-C₆ alkylene)-C(O)—OH, —(C₂-C₆ alkenylene)-N(R¹¹)(R¹²), —(C₂-C₆alkenylene)-C(O)—N(R¹¹)(R¹²), —(C₂-C₆ alkenylene)-C(O)—OH, —(C₂-C₆alkynylene)-N(R¹¹)(R¹²), —(C₂-C₆ alkynylene)-C(O)—N(R¹¹)(R¹²), —(C₂-C₆alkynylene)-C(O)—OH, —(C₀-C₆ alkylene)-aryl-N(R¹¹)(R¹²), —(C₀-C₆alkylene)-aryl-C(O)-aryl-N(R¹¹)(R¹²), —(C₀-C₆ alkylene)-aryl-C(O)—OH,—(C₂-C₆ alkenylene)-aryl-N(R¹¹)(R¹²), —(C₂-C₆alkenylene)-aryl-C(O)—N(R¹¹)(R¹²), —(C₂-C₆ alkenylene)-aryl-C(O)—OH,—(C₂-C₆ alkynylene)-aryl-N(R¹¹)(R¹²), —(C₂-C₆alkynylene)-aryl-C(O)—N(R¹¹)(R¹²), and —(C₂-C₆ alkynylene)-aryl-C(O)—OH;

R¹⁰ is hydrogen and when R⁹ is hydrogen or C₁-C₃ alkyl, R¹⁰ isadditionally selected from C₁-C₃ alkyl and phenyl optionally substitutedwith halogen or hydroxy; and when R⁹ and R¹⁰ are attached to adjacentring atoms, R⁹ and R¹⁰ are optionally taken together to form acarbocycle, aryl, heterocycle or heteroaryl fused to ring A, wherein thecarbocycle, aryl, heterocycle or heteroaryl is optionally substitutedwith one or more substituent selected from halo, —CN, —OH, —(C₀-C₆alkylene)-N(R¹¹)(R¹²), —(C₀-C₆ alkylene)-C(O)—N(R¹¹)(R¹²), —(C₀-C₆alkylene)-C(O)—OH, —(C₂-C₆ alkenylene)-N(R¹¹)(R¹²), —(C₂-C₆alkenylene)-C(O)—N(R¹¹)(R¹²), —(C₂-C₆ alkenylene)-C(O)—OH, —(C₂-C₆alkynylene)-N(R¹¹)(R¹²), —(C₂-C₆ alkynylene)-C(O)—N(R¹¹)(R²), —(C₂-C₆alkynylene)-C(O)—OH, —(C₀-C₆ alkylene)-S(O)₂—OH, —(C₂-C₆alkenylene)-S(O)₂—OH, —(C₂-C₆ alkynylene)-S(O)₂—OH, and —(C₀-C₆alkylene)-aryl-S(O)₂—OH;

each R¹¹ is independently selected from hydrogen, —C(O)—(C₁-C₄ alkyl),and —C₁-C₄ alkyl;

each R¹² is independently selected from hydrogen, —C₁-C₄ alkyl, —(C₀-C₄alkylene)-carbocycle, —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-heterocycle, —(C₀-C₄ alkylene)-heteroaryl, and wherein thecarbocyclyl, aryl, heteroaryl, or heterocyclyl portion of R² may befurther substituted with up to 4 substituents independently selectedfrom halogen, —CN, —OH, —COOH, —CONH₂, and C₁-C₃ alkyl; or Ru and R²together form a heterocyclic or heteroaromatic ring optionallysubstituted with one or more groups selected from halogen, —CN, —OH,—COOH, —CONH₂, and C₁-C₃ alkyl;

provided the compound comprises no more than two —S(O)₂—OH moieties.

In a fourteenth embodiment of the methods described herein, R⁷ instructural formula H or IIa is selected from —S(O)₂—OH and—CH₂—S(O)₂—OH, wherein the remaining variables are as described abovefor structural formula II or IIa.

In a fifteenth embodiment of the methods described herein, R⁸ instructural formula II or IIa is attached to a ring carbon and isselected from —NH₂, —CH₂NH₂, —C(O)NH₂, and —COOH, wherein the remainingvariables are as described above for structural formula II or IIa, orthe fourteenth embodiment thereof. In some aspects of the fifteenthembodiment, R⁸ in structural formula II or IIa is attached to a ringnitrogen and is selected from —CH₂NH₂, —CH₂C(O)NH₂, and —CH₂COOH,wherein the remaining variables are as described above for structuralformula II or IIa, or the fourteenth embodiment thereof.

In a sixteenth embodiment of the methods described herein, ring B instructural formula II or IIa is selected from pyrrole, pyrazole,imidazole, triazole, thiophene, thiadiazole, and thiazole, wherein theremaining variables are as described above for structural formula II orIIa, or the fourteenth or fifteenth embodiment thereof.

In a seventeenth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula II or IIa, wherein R⁹ and R¹⁰ are taken together with ring B toform a bicyclic, quaternary nitrogen-containing ring system, wherein theremaining variables are as described above for structural formula II orIIa. In some aspects of the seventeenth embodiment, the quaternarynitrogen is a ring atom in the ring B portion of the bicyclic ringsystem, wherein the remaining variables are as described above forstructural formula II or IIa. In some aspects of the seventeenthembodiment, the quaternary nitrogen is a bridgehead atom in the bicyclicring system, wherein the remaining variables are as described above forstructural formula II or IIa. In some aspects of the seventeenthembodiment, the quaternary nitrogen is a ring atom in the portion of thebicyclic ring system formed by taking R⁹ and R¹⁰ together, wherein theremaining variables are as described above for structural formula H orHa. In some aspects of the seventeenth embodiment, the quaternarynitrogen, when substitutable, is substituted with R¹⁰, wherein theremaining variables are as described above for structural formula II orIIa. In more specific aspects of the seventeenth embodiment, thequaternary nitrogen, when substitutable, is substituted with a C₁-C₄alkyl, wherein the remaining variables are as described above forstructural formula II or IIa. In still further specific aspects of theseventeenth embodiment, the compound of structural formula II has theformula:

or a pharmaceutically acceptable salt thereof, wherein:

ring C is a ring formed by taking together R⁹ and R¹⁰, wherein ring Coptionally comprises 1 to 2 ring nitrogen atoms in addition to thequaternary nitrogen;

R¹¹ is —(C₀-C₄ alkylene)-SO₃;

R¹² is selected from hydrogen, —(C₀-C₄ alkylene)-aryl, —(C₀-C₄alkylene)-heteroaryl, —(C₀-C₄ alkylene)-carbocyclyl, and —(C₀-C₄alkylene)-heterocyclyl; and

R¹⁵ is C₁-C₄ alkyl.

In an eighteenth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula II or IIa, wherein R⁷ is —SO₂—OH; and R⁸ is —NH₂; and whereinthe remaining variables are as described above for structural formula IIor IIa. In some aspects of the eighteenth embodiment, R⁹ and R¹⁰ areboth hydrogen, wherein the remaining variables are as described abovefor structural formula II or IIa.

In a nineteenth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula II or IIa, wherein R⁷ is —SO₂—OH; and ring B comprises a ringnitrogen bound to hydrogen; and wherein the remaining variables are asdescribed above for structural formula II or IIa. Examples of suchcompounds are:

In a twentieth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula II or IIa, wherein R⁷ is —SO₃; and R⁹ and R¹⁰ are taken togetherwith ring B to form a bicyclic, quaternary nitrogen-containing ringsystem; and wherein the remaining variables are as described above forstructural formula II or IIa. In some aspect of the twentiethembodiment, the ring formed by R⁹ and R¹⁰ is substituted with up to twoC₁-C₄ alkyl groups.

In a twenty-first embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula III:

or a pharmaceutically acceptable salt thereof, wherein:

ring D is phenyl, pyridyl, triazolyl, pyrazolyl, thiazolyl, triazinyl,pyrimidinyl, or thiophenyl;

q is 2, 3, or 4;

R¹⁶ is selected from (C₁-C₄)alkyl, —(C₁-C₄)alkylCOOR^(a),(C₁-C₄)alkylSO₃H, —O(C₁-C₄)alkyl, —SO₃H, —NR^(a)R^(b), —OR^(a),—COOR^(a), —COONR^(a)R^(b), morpholinyl, pyrazolyl, isoxazolyl, phenyl,and dihydropyrazolyl, wherein each of said morpholinyl, pyrazolyl,isoxazolyl, and phenyl are optionally substituted with 1 to 3 groupsselected from —NR^(c)R^(d), SO₃H, (C₁-C₄)alkyl, and —COOR^(c), andwherein said dihydropyrazolyl is optionally substituted with 1 to 3groups selected from oxo, —NR^(c)R^(d), SO₃H, (C₁-C₄)alkyl, and—COOR^(c);

R^(a) and R^(b) are each independently hydrogen, (C₁-C₄)alkyl, orphenyl, wherein said phenyl is optionally substituted with 1 or 2—NR^(c)R^(d) groups; and

R^(c) and R^(d) are each independently hydrogen or (C₁-C₄)alkyl.

In a twenty-second embodiment, R¹⁶ in the compound of structural formulaIII of the present methods is selected from (C₁-C₄)alkyl;(C₁-C₄)alkylCOOH; (C₁-C₄)alkylSO₃H; —O(C₁-C₄)alkyl; —SO₃H; NH₂;—NH(C₁-C₄)alkyl, OH; COOH; —NHphenyl; —NHphenyl(NH₂); —COOCH₃;COON(CH₃)₂; morpholinyl; pyrazolyl substituted with 1 or 2 groupsselected from (C₁-C₄)alkyl, NH₂, and COOEt; isoxazolyl substituted with1 or 2 (C₁-C₄)alkyl) groups; phenyl substituted with 1 or 2 groupsselected from (C₁-C₄)alkyl and SO₃H; and dihydropyrazolyl substitutedwith 1 or 2 groups selected from (C₁-C₄)alkyl, NH₂, oxo, and COOH,wherein the remaining variables are as described above for formula III.

In a twenty-third embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound of structuralformula IV:

or a pharmaceutically acceptable salt thereof, wherein:

ring E is benzoimidazolyl, indolinyl, naphthalenyl,dihydrobenzooxazinyl-2-one, benzothiazolyl, thiazolopyrimidinyl-4-ium,or benzoxazolyl;

t is 2, 3, or 4;

R¹⁷ is selected from (C₁-C₄)alkyl, —O(C₁-C₄)alkyl, —SO₃H,—(C₁-C₄)alkylSO₃H, —NR^(a)R^(b), and phenyl, wherein said phenyl isoptionally substituted with (C₁-C₄)alkyl or —NR^(a)R^(b); and

R^(a) and R^(b) are each independently hydrogen or (C₁-C₄)alkyl.

In a twenty-fourth embodiment, R¹⁷ in the compound of structural formulaIV of the present methods is selected from (C₁-C₄)alkyl, —SO₃H,—(C₁-C₄)alkylSO₃H, NH₂, and phenyl, wherein said phenyl is optionallysubstituted with NH₂, wherein the remaining variables are as describedabove for formula IV.

In a twenty-fifth embodiment, provided herein is a method of treating adisease characterized by amyloid aggregates comprising the step ofadministering to a subject in need thereof a compound as provided inTable 1, below. Neutral forms, salt forms, charged forms, hydrates, freebase forms and tautomeric forms of those compounds, where applicable,are included.

TABLE 1 Compound Structure 100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

3. Uses, Formulation, and Administration

In one aspect, the present disclosure provides the use of one or morecompounds described herein, or a pharmaceutically acceptable saltthereof, for treating a disease characterized by amyloid aggregates.Also provided is the use of one or more compounds described herein, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating a disease characterized by amyloid aggregates.

In one aspect, diseases characterized by amyloid aggregates include, butare not limited to, Alzheimer's disease including familial (hereditary)forms thereof, Down's syndrome dementia, Parkinson's Disease, Acutemacular degeneration (AMD), glaucoma, Inclusion Body Myositis (IBM),traumatic brain injury, Lewy Bodies dementia, Huntington's disease,Nieman-Picks Type C, Cerebral Amyloid Angiopathy (CAA),Creutzfeldt-Jakob disease, AA Amyloidosis, AL Amyloidosis, ATTRamyloidosis, Familial amyloid polyneuropathy (FAP), Familial amyloidcardiomyopathy (FAC), Senile systemic amyloidosis, and prion disease. Inone aspect, the disease characterized by amyloid aggregates isAlzheimer's disease.

Other diseases characterized by a pathophysiological link to amyloiddeposition, formation and/or potential for prion-like self-propagationare also included in the methods described herein.

Pharmaceutically acceptable carriers that may be used in thecompositions of this disclosure include, but are not limited to, ionexchangers, alumina, aluminum stearate, magnesium stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances (e.g., microcrystalline cellulose, hydroxypropylmethylcellulose, lactose monohydrate, sodium lauryl sulfate, andcroscarmellose sodium), polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

Method of administration can use an amount and a route of administrationeffective for treating or lessening the severity of one or more of thediseases and conditions described herein. The exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularagent, its mode of administration, and the like. Provided compounds arepreferably formulated in unit dosage form for ease of administration anduniformity of dosage. For example, provided compounds may be formulatedsuch that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.The expression “unit dosage form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present disclosure will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Method of administration to humans and other animals can be orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),buccally, as an oral or nasal spray, or the like, depending on theseverity of the infection being treated. In a more specific aspect, themethod of administration is oral.

EXEMPLIFICATION Synthetic Methods

Compounds described herein may be purchased commercially and/or preparedfollowing the general methods described below.

Oxidation of Heteroaromatic Thiols

Heteroaromatic thiols e.g., 4-amino-5-aryl-3-thiol-4H-1,2,4-triazole canbe oxidized from the appropriate thiol starting material using 30% H₂O₂in aq. acetic acid at e.g., room temperature. See Scheme 1 below for anon-limiting representation that can be generally applied to relatedstarting materials and products.

Sulfonation of Aminothiazoles

Aminoheterocycles e.g., aminothiazoles can be sulfonated by slowlyadding to the aminoheterocycle small portions to chlorosulfonic acidcooled (e.g., at −5 deg Celsius (C)) while stirring e.g., within 30minutes. After hydrogen chloride evolution is observed, the reactionmixture may then be stirred for 1 hour at room temperature. The reactionmay be slowly poured on crushed ice and neutralized by cooled NaOHsolution while temperature is maintained e.g., below 10 deg Celsius. Theprecipitate may be filtered and washed, e.g., with ethanol and water.See Scheme 2 below for a non-limiting representation that can begenerally applied to related starting materials and products.

Deprotection of Benzylthio Groups Followed by Oxidation to SulfonicAcids

Benzylthio groups may be converted to sulfonic acids using the followingmethods. A suspension of a benzylthio-compound in 50% aq. acetic acidmay be oxidized by chlorine for 30 minutes at e.g., 5 deg Celsius. Theproduct may be isolated via acidification with HCL. See Scheme 3 belowfor a non-limiting representation that can be generally applied torelated starting materials and products.

Synthesis of 2-(alkyl)amino-5-halo-3-pyridinesulfonic Acid

The corresponding 2-(alkyl)amino-5-halo-3-pyridine sulfonylchloride orsulfonamide can be subjected to acidic hydrolysis with HCl in aqueoussolution with added acetonitrile if needed to solubilize the compoundcompletely. The reaction can be carried out in room temperatureovernight to the completion. See Scheme 4 below for a non-limitingrepresentation that can be generally applied to related startingmaterials and products.

3-Sulfonation of Pyridine Derivatives

Direct sulfonylation of pyridine derivatives can be carried out inethanol solution with conc. Sulfuric acid and metal Aluminum for 5 hrsat a temperature of 210 deg C.

An alternative method to sulfonate a pyridine derivative is to add thepyridine derivative portionwise to oleum (sulfuric acid mixture withsulfur trioxide) over 30 min. The resulting solution can then be heatedto 140 deg C. for 4 hours. The reaction mixture can then be poured ontoice and the mixture can then be stirred in an ice bath (ice with salt)for another 2 hours. The resulted suspension can then be filtered, andthe solid washed with water and dried under suction. See Scheme 5 belowfor a non-limiting representation that can be generally applied torelated starting materials and products.

4- and 2-Sulfonation of Pyridine Derivatives

Based on a substitution pattern of the pyridine ring one can directsulfonylation to position 4. Direct sulfonylation can be carried out inoleum at 160 deg Celsius for 20 hours. 2-sulfonation e.g.,alkylpyridine-2-sulfonic acids can be prepared by takingalkyl-2-chloropyridine and dissolving it in water and reacting withsodium sulfite Na₂SO₃ at 190 deg Celsius for 20 hours under pressure of2 MPa. The resulting sodium sulfonate can be converted to thecorresponding sulfonic acid via acidic work up.

Sulfonation of Pyrimidine Derivatives

A pyrimidine derivative can be slowly dissolved in monochlorosulfuricacid at room temperature and then stirred at 150 deg Celsius for 8hours. The reaction mixture is cooled and worked up in a similar way asdescribed for pyridine-derived compounds above. The correspondingsulfonylchloride can then be hydrolyzed in water into the correspondingsulfonic acid. See Scheme 6 below for a non-limiting representation thatcan be generally applied to related starting materials and products.

Substitution of Heteroaromatic Halides with Substituted Amines

Corresponding halo-compounds can be reacted with an alcoholic solutionof the corresponding amine. See Scheme 7 below for a non-limitingrepresentation that can be generally applied to related startingmaterials and products.

Pd-Catalyzed Amination

Palladium catalyzed amination may be carried out on five-membered,six-membered, and aryl-fused heteroaromatic compounds described herein.Such methods are well-known to those skill in the art and include, butare not limited to, reacting an amine with an aromatic halide, triflate,or the like (designated by X) with a Pd(0) species, or Pd(0) formed insitu from Pd(II), and ligand optionally in the presence of base (e.g.,LHMDS) to form the corresponding amine. A precatalyst may also be added.A representative scheme is shown below as Scheme 8.

Palladium species are known in the art and include e.g., palladium(II)catalysts (e.g., bis(acetonitrile)palladium(II) chloride, palladium(II)acetate, palladium(II) bromide, palladium(II) chloride, palladium(II)trifluoroacetate, tetrakis(acetonitrile)palladium (II)tetrafluoroborate, [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), bis(triethylphosphine)palladium(II) chloride,bis(triphenylphosphine) palladium(II) acetate,bis(triphenylphosphine)palladium(II) chloride,bis[tri(o-tolyl)phosphine]palladium(II) chloride,dichlorobis(tricyclohexylphosphine)palladium(II), trans-benzyl (chloro)bis(triphenylphosphine)palladium(II), and the like or commerciallyavailable palladium(0) catalysts (e.g.,tris(dibenzylideneacetone)dipalladium(0), bis(tricyclohexylphosphine)palladium(0), bis(tri-t-butylphosphine)palladium(0),bis[1,2-bis(diphenylphosphino)ethane]palladium(0),tetrakis(triphenylphosphine)palladium(0), and the like.

Ligands and/or precatalysts for use in facilitating palladium-mediatedaminations may be monodentate or bidentate ligands. Examples include,but are not limited to,

RuPhos, t-BuXPhos, BrettPhos, AdBrettPhos, tBuBrettPhose, Me₄tBuXPhos,JohnPhos, and the like. Buchwald-Hartwig-type palladacycles may also beused.

Molecular Modeling

Molecular modeling to determine the degree to which the compounds usedin the methods described herein can bind to ß-amyloid can be performedusing the Schrödinger suite (Schrödinger Suite, 2015-3; Schrödinger,LLC: New York, N.Y., 2015). Molecular dynamics simulations can be runusing the algorithms described in Desmond Bowers, K. J. et al. ScalableAlgorithms for Molecular Dynamics Simulations on Commodity Clusters. SCConference, Proceedings of the ACMIEEE, IEEE 43-56 (2006). Thesimulations can be run on GeForce GTX Titan Black GPU cards. The OPLS3.0 force field (Shivakumar, D., Harder, E., Damm, W., Friesner, R. A. &Sherman, W. Improving the Prediction of Absolute Solvation Free EnergiesUsing the Next Generation OPLS Force Field. J. Chem. Theory Comput. 8,2553-2558 (2012)) can be used to model all interactions between thecompounds used herein and ß-amyloid, and the SPC model can be used forwaters. The 1IYT Aβ42 NMR structure from the PDB can be used as astarting point for MD simulations. This structure is primarily alphahelical and is representative of the peptide in an apolar environment. A20 Angstrom box of water or a mixed solvent box of 1% compound in watercan be added around the peptide using Schrödinger system setup tools.Ions can then be added to neutralize the charge of the entire system.Simulations were equilibrated and run under NPT conditions (constantpressure and temperature) with periodic boundary conditions. TheNose-Hoover Thermostat and Martina-Tobias-Klein barostat can be used tocontrol temperature and pressure, respectively. Simulations can be runin replicates of 3 for 100 nanoseconds each, and results compiled foranalysis. Principal component analysis can be performed using ProDy(Bakan, A., Meireles, L. M. & Bahar, I. ProDy: protein dynamics inferredfrom theory and experiments. Bioinformatics (Oxford, England) 27,1575-1577 (2011)) and plotted using custom python scripts.

Ion Mobility Mass Spectrometry (IMS MS)

Ion Mobility Mass Spectrometry can be used to assay the interactionbetween the compounds used in the present invention and beta-amyloid,namely amyloid beta (1-42), (or Aß42), amyloid beta (1-40) andpGlu-amyloid.

The conditions used for mass spectrometry can be as follows: WatersSynapt G2-S, positive polarity in sensitivity mode, capillary=2.5 kV,nebulizer=2 mbar, source temperature=80° C., desolvation temperature=60°C., sample cone setting=35 V, source offset setting=60 V, mass range=500to 4000 m/z. These conditions can be maintained throughout the study toensure consistency of the data and to avoid influencing the detection ofoligomers due to preferential ionization conditions.

Samples can be directly infused into the mass spectrometer at a flowrate of 10 μL/min using a PM-1000 Syringe Pump and Hamilton 1 mLSyringe. The data acquisition of the amyloid peptide can be performedusing a Waters Synapt G2-S quadrupole time of flight mass spectrometer(Q-TOF MS) with traveling wave ion mobility (Waters Corp. 34 MapleStreet Milford, Mass. 01757). The data can be acquired using the systemssensitivity mode to allow for the detection of the less abundantoligomers. Samples can be infused at room temperature.

Sample Preparation

One mg of recombinant human β-amyloid peptide (1-42) from BioLegend (99%purity, cat: 843801) can be reconstituted in 200 μL of Fisher OptimaLC/MS grade water (cat: W6-1) and vortexed vigorously for 2 minutes tosolubilize the peptide creating a 5 mg/mL solution. Samples can then bediluted to a final concentration of 22 pmol/μL prior to incubation. Thesample mixtures can then be incubated at room temperature for 0, 4 and24 hours, respectively. When the acquisition of the incubated samples iscompleted the raw data can be analyzed using the Waters MassLynx v2.4suite with DriftScover v2.7 to visualize drift times for the peptide.

Aß42 Species Characterization

Aß42 species characterization using IMS MS can be performed by directinfusion of the peptide at 22 pmol/μL in H₂O. The peptide can beprepared in H₂O to maintain the native state conformation of the peptidefor the ion mobility data acquisition. Ion mobility data acquisition canbe performed to detect and characterize the conformational changes ofthe native state monomer and any oligomers that may have formed duringthe incubation.

Binding Assay

The activity of the compounds utilized in the methods described hereincan be assayed by measuring the binding of those compounds to ß-amyloid.Data acquisition can be performed using a Waters Synapt G2-S quadrupoletime of flight mass spectrometer (Q-TOF MS) with traveling wave ionmobility (Waters Corp. 34 Maple Street Milford, Mass. 01757). The datacan be acquired using the systems sensitivity mode to allow for thedetection of the less abundant oligomers. Samples can be infused at roomtemperature due to lower solubility of the peptide at body temperature(37° C.).

One mg of compound can be reconstituted in 1 mL of Fisher Optima LC/MSgrade water (cat: W6-1) and vortexed vigorously for 2 minutes untilcompletely dissolved. The sample can be then diluted to create a 220pmol/μL, 2200 pmol/μL, and 22,000 pmol/μL solutions to perform bindingexperiments to Aß42 with 10-, 100-, and 1000-fold molar excess of testedcompound.

One mg of recombinant human β-Amyloid Peptide (1-42) from BioLegend canbe reconstituted in 200 μL of Fisher Optima LC/MS grade water andvortexed vigorously to solubilize the peptide creating a 5 mg/mLsolution. Samples can be then diluted to a final concentration of 44pmol/μL prior to mixing (1:1) with test compound solution. Finalconcentrations were 22 pmol/μL for human β-Amyloid Peptide (1-42) and1100 pmol/μL for test compounds.

The data acquisition was performed using a Waters time of flight massspectrometer (Q-TOF Micro). The data was acquired using the scanningmode to allow for the detection of the peptide. Samples were infused atroom temperature. The mass spectrometer conditions were maintainedthroughout the study to ensure consistency of the data. The Waters Q-TOFconditions were as follows:

Positive Polarity in sensitivity mode Capillary 3.5 kV Desolvation gasflow 500 L/Hr Cone gas flow  50 L/Hr Source Temperature 150° CDesolvation Temperature  60° C Sample cone setting 35 V Extraction conesetting  3 V Mass Range 1475 to 2000 m/z

Samples were directly infused into the mass spectrometer at a flow rateof 20 μL/min using in-build Syringe Pump and Hamilton 1 mL Syringe andthe acquisition time was kept 2 minutes. The results for Compounds117-172 are shown in Table 2, below:

TABLE 2 Number of Molecules Bound to Aβ1-42 # of Molecules CompoundBound to Aβ 117 3 118 1 119 0 120 8 121 0 122 0 123 ND 124 3 125 0 126 1127 0 128 0 129 ND 130 0 131 0 132 ND 133 0 134 2 135 0 136 0 137 0 1380 139 0 140 0 141 0 142 2 143 0 144 0 145 0 146 0 147 ND 148 5 149 0 1500 151 0 152 1 153 5 154 1 155 ND 156 ND 157 ND 158 0 159 ND 160 1 161 0162 ND 163 0 164 0 165 1 166 2 167 0 168 0 169 ND 170 6 171 7 172 0

Short Term Treatment in Adult Transgenic CRND8 Mice Overexpressing βAPP

Transgenic mice, TgCRND8, expressing the human amyloid precursor protein(hAPP) develop a pathology resembling Alzheimer's disease. Inparticular, high levels of Aß40 and Aß42 have been documented in theplasma and the brain of these animals at 8-9 weeks of age, followed byearly accumulation of amyloid plaques similar to the senile plaquesobserved in AD patients. These animals also display progressivecognitive deficits that parallel the appearance of degenerative changes.See, e.g., (Chishti, et al., J. Biol. Chem. 276, 21562-70 (2001).

The short term therapeutic effect of the compounds described herein canbe studied by administration over a 14 or 28 day period at the end ofwhich the levels of Aß peptides in the plasma and brain of TgCRND8animals are then determined.

Male and female transgenic mice from the 3^(rd) and 4^(th) B6C3F1generations can be used and given daily subcutaneous or oraladministrations of one of a series of compounds for 14 or 28 days. Thefollowing abbreviations can be used to designate these animals from the3^(rd) and 4th generation backcross in the present protocol:TgCRND8-2.B6C3F1(N₃); TgCRND8-2.B6C3F1(N₄).

Baseline animals (control group) may consist of naive TgCRND8-2.B6C3F1(N₃) at 11±1 weeks of age. These mice can be used to determine theAβ levels in the plasma and brain of naive transgenic animals at theinitiation of treatment.

Starting at 11 weeks of age (±1 week) animals receive dailyadministration of their respective treatment for a period of 14 or 28days, at a dose of 250 mg/kg at 10 ml/kg of compounds, or of vehicleonly (control group 2) or 1% methyl cellulose only (control group 3).The route of administration can be subcutaneous for water-solublecompounds and oral for compounds solubilized in methylcellulose 1% (MC1%). At the end of the treatment periods, plasma and perfused brains arecollected for quantification of Aβ levels.

All animals will be examined daily for signs of ill health when handledin the morning for their daily treatment and twice a day for mortalitychecks (once daily during weekends and holidays). Detailed examinationsare then performed on the treatment initiation, weekly during the study,and once before terminal procedures. More frequent observations can beundertaken when considered appropriate. Death and all individualclinical signs will be individually recorded. Individual body weightsare recorded at randomization, once weekly during the study, and oncebefore terminal procedures.

At 11±1 weeks of age for the Baseline group, and 24 hours after the endof the treatment period (14 or 28 days) for the other animals includingcontrol Groups 2 and 3, animals are sacrificed and samples collected. Anapproximate blood volume of 500 μl will be collected from the orbitalsinus and kept on ice until centrifugation at 4° C. at a minimum speedof 3,000 rpm for 10 minutes. Plasma samples are immediately frozen andstored at −80° C. pending analysis. The brains are then removed, frozen,and stored at −80° C. prior to analysis.

Brains are weighed, frozen and homogenized with 4 volumes of ice cold 50mM Tris-Cl pH 8.0 buffer with protease inhibitor cocktail (4 mL ofbuffer for 1 g of wet brain). Samples are spun at 15000 g for 20 minutesand the supernatants are transferred to fresh tubes. One hundred fifty(150) μl from each supernatant are then mixed with 250 μl of 8Mguanidine-HCL/50 mM Tris-HCL pH 8.0 (ratio of 0.6 vol supernatant:1 vol8M guanidium/Tris-HCL 50 mM pH8.0) and 400 μL 5 M guanidium/Tris-HCl 50mM pH8.0 are added. The tubes are vortexed for 30 seconds and frozen at−80° C. In parallel, pellets are treated with 7 volumes of 5 Mguanidine-HCL/50 mM Tris-HCL pH 8.0 (7 mL of guanidine for 1 g of wetbrain), vortexed for 30 seconds and frozen at −80° C. Samples are thawedat room temperature, sonicated at 80° C. for 15 minutes and frozenagain. This cycle can then be repeated 3 times to ensure homogeneity andsamples were returned to −80° C. prior to analysis.

Aβ levels are evaluated in plasma and brain samples by ELISA using HumanAβ40 and Aβ42 Fluorometric ELISA kits from Biosource (Cat. No. 89-344and 89-348) according to manufacturer's recommended procedures. Samplesare thawed at room temperature, sonicated for 5 minutes at 80° C.(sonication for brain homogenates; no sonication for plasma samples) andkept on ice. Aß peptides are captured using 100 μl of the dilutedsamples to the plate and incubated without shaking at 4° C. overnight.The samples are aspirated and the wells are rinsed 4 times with washbuffer obtained from the Biosource ELISA kit. The anti-Aß40 or anti-Aß42rabbit polyclonal antiserum (specific for the Aß40 or Aß42 peptide) isadded (100 μl) and the plate is incubated at room temperature for 2hours with shaking. The wells are aspirated and washed 4 times beforeadding 100 μL of the alkaline phosphatase labeled anti-rabbit antibodyand incubating at room temperature for 2 hours with shaking. The platesare then rinsed 5 times and the fluorescent substrate (100 μL) is addedto the plate. The plate is incubated for 35 minutes at room temperatureand the plate can then be read using a titer plate reader at anexcitation wavelength of 460 nm and emission at 560 nm.

Compounds can be scored based on their ability to modulate levels of Aßpeptides in the plasma and the cerebral soluble/insoluble levels in thebrain. Levels of Aß observed in the plasma and brain of treated animalscan be normalized using values from vehicle-treated (water) ormethylcellulose-treated control groups and can be ranked according tothe strength of the pharmacological effect.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) that may be cited throughout this application are herebyexpressly incorporated herein in their entireties by reference. Unlessotherwise defined, all technical and scientific terms used herein areaccorded the meaning commonly known to one with ordinary skill in theart.

1.-25. (canceled)
 26. A method of treating Alzheimer's diseasecomprising the step of administering to a subject in need thereof acompound selected from:

or a pharmaceutically acceptable salt of any of the foregoing.
 27. Themethod of claim 26, wherein the compound is selected from:

or a pharmaceutically acceptable salt of any of the foregoing.
 28. Themethod of claim 26, wherein the compound is formulated into apharmaceutically acceptable composition additionally comprising apharmaceutically acceptable carrier.
 29. The method of claim 27, whereinthe compound is formulated into a pharmaceutically acceptablecomposition additionally comprising a pharmaceutically acceptablecarrier.